THE OFFICIAL NEWS SOURCE OF ACR CONVERGENCE 2022 • NOVEMBER 10-14



Genomic, epigenomic research into underpinnings of RA show therapeutic promise

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Gary Firestein, MD

This year’s recipient of the Rheumatology Research Foundation Paul Klemperer, MD, Memorial Lectureship, Gary Firestein, MD, dedicated his lecture Sunday to an explanation of research into how the human genome, epigenome, and environmental factors lead to the development and progression of RA and how this research can improve therapy.

Dr. Firestein, Professor, Dean, and Associate Vice Chancellor of Translational Medicine at the University of California, San Diego, and his research group have conducted extensive research into the role that genes and epigenetic factors play in RA. He defines epigenetics as heritable changes in gene activity not caused by changes in DNA.

The UCSD researchers have focused on fibroblast-like synoviocytes (FLS) in arthritis and have found that RA FLS are epigenetically imprinted in early disease and evolve over time and that peripheral blood monocytes might be used to assess the epigenome of joints.

Some genes associated with RA have already been identified through genome-wide association studies, such as PTPN11 and LBH genes. Potential therapeutic targets for RA do not need to be the genes themselves, but could be something in the underlying genetic signaling pathways to the disease. Dr. Firestein said.

“Therapy could directed at reverting the methylome,” he said. Methylomes consist of the set of nucleic acid methylation modifications in an organism’s genome or in a particular cell.

There are disease-independent and disease-specific differences in the FLS of the knee versus the hip joint, he has found. Disease-independent differences are related to genes involved with differentiation, such as multiple HOX genes and WNT genes. Disease-specific differences are related to genes involved in cytokine signaling, including IL-6-JAK signaling pathways, IL-17 signaling pathways, and IL-22 signaling pathways.

“These differences could explain regional differences in RA joint distribution and asynchronous clinical responses to therapeutic agents,” he said.

Because of the complexity of finding the next generation of therapeutic targets for RA, computational approaches are necessary, including RNA sequencing of the transcriptome, whole-gene bisulfate sequencing of DNA methylation, and ChIP sequencing of histone marks, he believes.

His group’s research suggests that the RA epigenetic landscape is imprinted in FLS with distinctive chromatin states that can be detected using DNA methylation, histome marks, and sequencing for open chromatin. RA chromatin states can potentially reveal key signaling pathways relevant to RA, as well as potential therapeutic targets and information on the pathogenesis of the disease.

In addition, DNA methyltransferases and histone-modifying enzymes might be used to remodel RA chromatin states.

“Systems biology can potentially be useful in evaluating potential targets. We are looking at combination approaches to revert the RA phenotype and identify novel targets. We could possibly repurpose drugs with limited efficacy or toxicity in RA and take advantage of synergy” when used with existing RA drugs, Dr. Firestein said.

Systems biology might also be used to identify key interactions among genetic signaling pathways that can be modified to revert an aggressive RA FLS phenotype to a normal phenotype.

The next steps in identifying therapeutics are to expand epigenetic studies to identify additional genes associated with RA and develop biologic approaches to validate potential targets in cells and pre-clinical models, he said.